A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism

Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-cycloserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate this paper to Ole Ivar Lovaas (May 8, 1927-August 2, 2010), a pioneer in the field of autism. © 2011 Elsevier Ltd.

Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-cycloserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate this paper to Ole Ivar Lovaas (May 8, 1927-August 2, 2010), a pioneer in the field of autism. © 2011 Elsevier Ltd.

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